I. Field of the Invention
The present disclosure relates generally to the fields of chemistry, biology and medicine. More particularly, it concerns β-lactam compounds, compositions and methods for the treatment and prevention of diseases such as cancer, including pancreatic cancer and gemcitabine-resistant pancreatic cancer.
II. Description of Related Art
Pancreatic cancer is a malignant neoplasm of the pancreas. The prognosis is poor. Save in the lesser instance of success when these tumors are diagnosed early and in highly localized presentation the vast majority of patients die in a relatively short time. In part this is because the cancer usually causes no symptoms early on, leading to locally advanced or metastatic disease at time of diagnosis. Complete remission is still rare. Several human pancreatic cancer lines are highly resistant to gemcitabine (GEM). Accordingly, identifying and developing therapies that may be used to treat this disease would be highly desirable.
In general, β-lactams have many medicinal applications (Southgate et al., 1993; Kidwai et al., 1999; Bose et al., 2000; Banik, 2004). The need for potent β-lactam antibiotics and effective β-lactamase inhibitors has challenged chemists to design novel β-lactams (Buynak, 2004). These compounds have served as useful in the preparation of many heterocyclics of medicinal significance (Manhas et al., 2000; Bose et al., 2000; Ojima, 1995; Banik et al., 1994; Banik et al., 1993). Hydroxy β-lactam derivatives have been used as the starting materials in the semi synthesis of paclitaxel (Taxol) and docetaxel (Taxotere) (Suffness, 1995). The clinical use of β-lactams as therapeutic agents for lowering plasma cholesterol levels has been published (Clader et al., 1996; Burnett et al., 1994; Burnett, 2004; Clader, 2004). The biological activities of β-lactams against human leukocyte elastase have also been reported (Finke et al., 1995). Developing new β-lactams analogs, especially ones with potent anti-cancer properties, would be highly desirable.
Despite decades of the most intensive research and clinical efforts, our increasing ability to identify molecular targets putatively associated with key pathways in the development and lethal spread of cancer, and a myriad of claims of success, our struggle to contain, reverse or as in our most extreme expectations cure cancer have proven to be minimally successful. In the majority of human tumors derived from origins in various organs we have been able to slow recurrence, alleviate symptoms to a minor degree and delay death. On top of this dismaying picture, drugs that appeared to have a logical mode of action and initially promising results often prove to be of minimal efficacy and are removed from availability. The anti-angiogenic drug Avastin has been removed from use against breast cancer within the month (December 2010).
To further intensify this dilemma there are human cancers such as those arising in the pancreas and glioblastoma of the brain for which no available therapy is currently available. The National Cancer Institute has published estimates that 18,770 men and 18,030 women in the United States would die of pancreatic cancer annually. When compared with a detection rate of approximately 45,000 cases per year this demonstrates the devastating effect of this tumor. It represents the fourth leading cause of deaths worldwide. The median survival duration from diagnosis to death is approximately 6 months and the overall five-years survival is less than 5% (Jia et al., 2010; Li and Abbruzzese, 2010; Tran et al., 2010).
In addition to its early silent growth, treatment is complicated by its initial resistance to almost all available drugs and it remarkable ability to develop resistance to available main-line therapies within months of the onset of treatment (Tran et al., 2010; Kunnumakkara et al., 2010). Despite the most intensive investigation using all target pathways (Wan et al., 2010; Glazer et al., 2010 and Stadel et al., 2010) there is not a single agent available that has any significant effect on growing pancreatic cancer cells in animals or humans.